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Research Project: Metabolic and Epigenetic Regulation of Nutritional Metabolism

Location: Children's Nutrition Research Center

2023 Annual Report

We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4)identify by which amino acids, regulate protein synthesis, degradation, and accretion and how responses change with age;5)removed due to investigator departure;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces gluconeogenesis;10)study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway;11)alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study the functional impact of folic acid supplementation and in intestinal carcinogenesis;14)study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)removed due to investigator departure;17)study the CNS circuit architecture and explore circuit complexities that regulate non-homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19)study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods.

This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior.

Progress Report
To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), 3092-51000-065-03S (Project #3) and 3092-51000-065-04S (Project #4).

1. Researchers discover trouble in the epigenetics toolbox. Epigenetics describes the molecular mechanisms that enable our different cell types to develop and stably maintain different structures and functions. For more than a decade, researchers worldwide have been performing population studies to detect associations between DNA methylation (the most stable epigenetic mark) and disease; and nearly all these studies have used the same commercial methylation arrays. Scientists at the Children's Nutrition Research Center (CNRC) in Houston, Texas, reported that these arrays are not appropriate for population epigenetics, because 95% of the genomic sites they target do not show appreciable interindividual variation among humans (without interindividual variation, detecting associations is impossible). Additionally, we validated an innovative approach for studying Correlated Regions of Systemic Interindividual epigenetic Variation (CoRSIVs, which CNRC scientists discovered in 2019) and demonstrated the superiority of targeting CoRSIVs by documenting over 70-fold more genetic influence on human DNA methylation than had been previously documented. These advances call into question the results of over 1,000 studies of population epigenetics conducted over the last decade. A new product being marketed makes this technology available to epigenetic epidemiologists worldwide, helping the field of science to move forward.

2. A robust and integrative database framework to quickly find and use/integrate heterogeneous data. Investigating the complexities of nutrition benefits and rare diseases is akin to piecing together an intricate jigsaw puzzle and each fragment of this puzzle represents information gathered from a multitude of research studies. Despite numerous analytical standards, datasets, and tools, the scientific community often struggles to efficiently comprehend these vast data sources. To address these challenges, researchers at the Children's Nutrition Research Center in Houston, Texas, have developed an integrative database framework that meticulously organizes scientific information, including gene expression profiles. A significant problem we successfully tackled is the issue of "batch effects," which can introduce potential biases when integrating evidence from different scientists; our framework allows us to identify and account for these effects, enabling the discovery of recurring patterns in gene behaviors that individual studies might miss due to their limited scope. In essence, our newfound approach empowers scientists to gain a more comprehensive understanding of specific nutrients or diseases by examining a wide range of data. Our methodology offers a more efficient pathway for the scientific community to explore critical biological questions, ultimately benefiting farmers and consumers with precise dietary recommendations and nutritional planning.

3. Stress hormone promotes gut development in preterm pigs. Bile production is critical for fat digestion in newborn infants. Researchers at the Children's Nutrition Research Center in Houston, Texas have discovered that a stress hormone regulates the production of a novel gut hormone, Fibroblast Growth Factor 19 (FGF19) that is important in controlling the amount of bile made in the liver. Preterm piglets were used as a model for human infants to show that prematurity reduces the secretion of FGF19. The findings show that vaginal birth and production of the stress hormone, cortisol, during labor strongly stimulate the production of FGF19 in the blood. Treatment of intestinal cells with this stress hormone induce secretion of FGF19. Glucocorticoids, like cortisol, are frequently given to expectant preterm mothers and their newborn infants after birth to accelerate lung maturation. This finding points to cortisol treatment as a potential opportunity to also regulate FGF19, which may be valuable to improve growth, metabolic and hepatic outcomes in preterm babies. These findings are exciting because they could be an important step toward improved neonate care, particularly preterm neonates

4. Parent struggles in caring for children with severe obesity. Parents of children under five years of age with severe obesity must implement lifestyle changes at different developmental stages for potentially long periods of time. Since little data exists on the experiences of these parents as they care for their children, researchers at the Children's Nutrition Research Center in Houston, Texas, performed interviews with parents of children having early-onset obesity. Researchers found that mothers struggled with frequent blaming by their friends, family, and many medical professionals and felt unheard by the medical community. Mothers were also highly motivated to protect their child’s self-esteem, even from perceived damage by doctors, nurses, and dietitians. These results are important as they convey the great effort mothers are making in caring for their children and point to a great need by the medical community to provide individualized and compassionate care to obese children and their families.

5. Metreleptin treatment reduces gluconeogenesis in patients with lipodystrophy. Lipodystrophy is a rare disease characterized by deficiencies of adipose tissue and the hormone leptin, resulting in metabolic derangements akin to obesity-associated metabolic syndrome. Individuals with lipodystrophy are treated with a synthetic analog of leptin (metreleptin) to improve blood sugar (glucose) control and decreases energy expenditure. Scientists at the Children's Nutrition Research Center in Houston, Texas, demonstrated that metreleptin treatment in those with lipodystrophy reduced glucose production in the liver, likely through the decreased availability of carbon sources typically found in proteins. Additionally, scientists showed that metroleptin improved insulin sensitivity and markers of glucose control. Our findings provide insights for future research to find effective treatments for leptin deficient conditions. The data from our study supports the role of protein breakdown in insulin resistance conditions and suggests that therapeutic interventions targeting protein breakdown may improve blood sugar control.

6. Increased circulatory non-hydroxylated bile acids are associated with increased insulin sensitivity in humans. Bile acids are steroid acids that are produced in the liver and there is substantial data linking bile acids to obesity and diabetes risk. Insulin resistance is a condition when cells do not respond efficiently to insulin and are unable to easily take up glucose from the blood. Insulin resistance has been shown to be associated with an increased concentration of certain hydroxylated bile acids. Scientists at the Children's Nutrition Research Center in Houston, Texas, showed that different genetic mutations in humans was associated with an increase in non-hydroxylated bile acids and increased insulin sensitivity. This finding related to bile acids serves as a potential novel target for future therapeutic intervention for diabetes.

7. Glycine synthesis is reduced in adults with morbid obesity and increases following bariatric surgery. Insulin resistance is a condition when cells in muscles, fat, and liver do not respond efficiently to insulin and are unable to easily take up glucose from blood. Obesity is a risk factor for insulin resistance and is associated with disturbances in the metabolism of not only glucose and lipids, but also of certain amino acids. Scientists at the Children’s Nutrition Research Center in Houston, Texas, demonstrated that low plasma glycine concentration in humans with severe obesity and insulin resistance is associated with impaired glycine synthesis, which is improved after bariatric surgery. This finding implies that glycine may be a conditionally essential amino acid in obesity. Additionally, it has important human implications since plasma glycine concentrations can be raised by simple measures such as dietary supplementation

8. Acanthosis nigricans predicts low vitamin D levels in children. Vitamin D deficiency can cause significant health problems, including the bone disease rickets; yet guidelines differ on when children should be screened for vitamin D deficiency. Acanthosis nigricans, a darkening of skin around the neck, correlates with low vitamin D levels in predominantly white children but it was unknown if acanthosis nigricans could be used as a clinical sign to predict low vitamin D levels in children with darker skin tones (like Hispanic or Black children). Researchers at the Children's Nutrition Research Center in Houston, Texas, found that low vitamin D levels were 3.6 times more likely in minority children with acanthosis nigricans. This research further supports that children with acanthosis nigricans should have vitamin D levels checked routinely as they may be more at risk of vitamin D deficiency.

Review Publications
Vonderohe, C., Guthrie, G., Stoll, B., Melendez Hebib, V., Dawson, H.D., Burrin, D.G. 2022. Increased circulating cortisol after vaginal birth is associated with increased FGF19 secretion in neonatal pigs. Endocrinology. 164(1).
Perez, K., Valentine, G.C., Nangia, S., Burrin, D.G., Maheshwari, A., Abayneh, M., Workneh, R., Jerome, M., Dinerstein, A., Salas, A. 2022. Advancement of enteral feeding in very-low-birth-weight infants: Global issues and challenges. Newborn.
Lin, S., Wang, S., Wang, P., Tang, C., Wang, Z., Chen, L., Luo, G., Chen, H., Liu, Y., Feng, B., Wu, D., Burrin, D.G., Fang, Z. 2022. Bile acids and their receptors in regulation of gut health and diseases. Progress in Lipid Research. 89. Article 101210.
Gunasekara, C., MacKay, H., Scott, C., Li, S., Laritsky, E., Baker, M., Grimm, S.L., Jun, G., Li, Y., Chen, R., Wiemels, J.L., Coarfa, C., Waterland, R.A. 2023. Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control. Genome Biology. 24. Article 2.
Melendez Hebib, V., Taft, D., Stoll, B., Liu, J., Call, L., Guthrie, G., Jensen, N., Hair, A.B., Mills, D.A., Burrin, D.G. 2023. Probiotics and human milk differentially influence the gut microbiome and NEC incidence in preterm pigs. Gut Microbes. 15(11):2585.
Ismail, H.M., Barua, S., Wang, J., Sabharwal, A., Libman, I., Bacha, F., Nadeau, K.J., Tosur, M., Redondo, M.J. 2023. Baseline leptin predicts response to metformin in adolescents with type 1 diabetes and increased body mass index. Diabetes Obesity and Metabolism.
Rudar, M., Suryawan, A., Nguyen, H.V., Chacko, S.K., Vonderohe, C., Stoll, B., Burrin, D.G., Fiorotto, M.L., Davis, T.A. 2023. Regulation of skeletal muscle protein synthesis in the preterm pig by intermittent leucine pulses during continuous parenteral feeding. American Society for Parenteral and Enteral Nutrition.
Rambout, X., Cho, H., Blanc, R., Lyu, Q., Miano, J.M., Chakkalakal, J.V., Nelson, G.M., Yalamanchili, H.K., Adelman, K., Maquat, L.E. 2023. PGC-1alpha senses the CBC of pre-mRNA to dictate the fate of promoter-proximally paused RNAPII. Molecular Cell. 83(2):186-202.
Zhong, S., Chevre, R., Castano Mayan, D., Corliano, M., Cochran, B.J., Ping Sem, K., Van Dijik, T.H., Peng, J., Juin Tan, L., Hartimath, S.V., Ramasamy, B., Cheng, P., Groen, A.K., Kuipers, F., Goggi, J.L., Drum, C., Van Dam, R.M., San Tan, R., Rye, K., Hayden, M.R., Cheng, C., Chacko, S., Flannick, J., Sim, X., Chang Tan, H., Singaraja, R.R. 2022. Haploinsufficiency of CYP8B1 associates with increased insulin sensitivity in humans. Journal of Clinical Investigation. 132(21). Article e152961.
Nadeau, K.J., El Ghormli, L., Arslanian, S., Bacha, F., Caprio, S., Chan, C., Chao, L.C., Rayas, M., Siska, M.K., Zeitler, P. 2023. Effect of early glycemic control in youth-onset type 2 diabetes on longer-term glycemic control and b-cell function: Results from the TODAY Study. Diabetes Care. 46(8):1507-1514.
Jonnakuti, V.S., Ji, P., Gao, Y., Lin, A., Chu, Y., Elrod, N., Huang, K., Li, W., Yalamanchili, H.K., Wagner, E.J. 2023. NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1. Journal of Neuro-Oncology.
Tan, H.C., Hsu, J.W., Tai, E., Chacko, S., Wu, V., Lee, C.F., Kovalik, J., Jahoor, F. 2022. De novo glycine synthesis is reduced in adults with morbid obesity and increases following bariatric surgery. Frontiers in Endocrinology. 9(13). Article 900343.
Christiansen, L.I., Holmqvist, B., Pan, X., Holgersen, K., Lindholm, S.E., Henriksen, N.L., Burrin, D.G., Ley, D., Thymann, T., Sangild, P., Pankratova, S. 2023. Insulin-like growth factor-1 supplementation promotes brain maturation in preterm pigs. eNeuro. 10(4):1-15.
De Prisco, N., Ford, C., Elrod, N.D., Lee, W., Tang, L.C., Huang, K., Lin, A., Ji, P., Jonnakuti, V.S., Boyle, L., Cabaj, M., Botta, S., Yalamanchili, H.K. 2023. Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites. Science Advances. 9(7). Article eade4814.
MacKay, H., Gunasekara, C.J., Yam, K., Srisai, D., Yalamanchili, H.K., Li, Y., Chen, R., Coarfa, C., Waterland, R.A. 2022. Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index. Science Advances. 8(39).
El-Ayash, H., Puyau, M., Bacha, F. 2023. Hyperglycemia: A determinant of cardiac autonomic dysfunction in youth with obesity across the spectrum of glycemic regulation. Pediatric Obesity. Article e13063.
Yang, L., Chen, X., Lee, C., Shi, J., Lawrence, E.B., Zhang, L., Li, Y., Gao, N., Jung, S., Creighton, C.J., Li, J., Cui, Y., Arimura, S., Lei, Y., Li, W., Shen, L. 2023. Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer. Journal of Experimental and Clinical Cancer Research. 42. Article 113.
Gencel-Augusto, J., Su, X., Qi, Y., Whitley, E.M., Pant, V., Xiong, S., Shah, V., Lin, J., Perez, E., Fiorotto, M.L., Jain, A.K., Lorenzi, P.L., Navin, N.E., Richie, E.R., Lozano, G. 2023. Dimeric p53 mutant elicits unique tumor-suppressive activities through an altered metabolic program. Cancer Discovery. 13(5):1230-1249.
Vonderohe, C., Guthrie, G., Burrin, D.G. 2023. Fibroblast growth factor 19 secretion and function in perinatal development. American Journal of Physiology - Gastrointestinal and Liver Physiology. 324(3):G190-G195.
Bryant, K., Sandhu, J., Nguyen, J., Asonye, E., Thompson, D.J., Sisley, S. 2022. Isolation in a sea of "experts": Identifying the parental struggles caring for children with early-onset obesity. Childhood Obesity.
Demello, A.S., Acorda, D.E., Thompson, D.J., Allen, D.L., Aman, R., Brandt, M.L., Sisley, S. 2022. Growing up after adolescent bariatric surgery. Clinical Nursing Research.
Bacha, F., El Ghormli, L., Braffett, B.H., Shah, A.S., Marcovina, S.M., Levitt Katz, L.E., Willi, S.M., Caprio, S., Dhaliwal, R., Gidding, S.S., for the Today Study Group. 2023. Candidate biomarkers as predictors of future kidney disease and cardiovascular dysfunction in adolescents with type 2 diabetes. Diabetes Research and Clinical Practice. 199. Article 110671.
Trostle, A., Li, L., Kim, S., Wang, J., Al-Ouran, R., Yalamanchili, H.K., Liu, Z., Wan, Y. 2023. A comprehensive and integrative approach to MeCP2 disease transcriptomics. International Journal of Molecular Sciences. 24(6). Article 5122.
Christiansen, L.I., Ventura, G.C., Holmqvist, B., Aasmul-Olsen, K., Lindholm, S.H., Lycas, M.D., Mori, Y., Bojsen-Møller Secher, J., Burrin, D.G., Thymann, T., Sangild, P., Pankratova, S. 2023. Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs. Frontiers in Neuroscience. 17. Article 1205819.
Moran, N.E., Wade, J., Stroh, R., Stoll, B., Guthrie, G., Hair, A.B., Burrin, D.G. 2023. Preterm pigs fed donor human milk have greater liver beta-carotene concentrations than pigs fed infant formula. Journal of Nutrition.
Wesenberg Helt, T., Buelund, L., Borgewardt, L., Eriksen, T., Johansen, L., De Nijs, R., Holm, S., Burrin, D.G., Thymann, T., Brix Christensen, V. 2023. Towards a model of biliary atresia - pilot feasibility study in newborn piglets. Biochemistry and Biophysics Reports. 34. Article 101487.
Castillo Rodriguez, B., Astudillo, M., Tosur, M., Rafaey, A., McKay, S., Bacha, F., Balasubramanyam, A., Redondo, M.J. 2023. Characteristics of type 2 diabetes in female and male youth. Clinical Diabetes. 41(2):239–243.